ISSCR Draft-Guidelines-for-Stem-Cell-Science-and-Clinical-Translation

1. Dear Reader,
We invite you to consider and provide feedback on the following draft of the ISSCR’s “Guidelines
for Stem Cell Research and Clinical Translation.” These guidelines represent an effort by a
Guidelines Revision Task Force, working on behalf of the ISSCR Board of Directors and the ISSCR
membership, to revise and update our existing guidance documents in response to the evolving
scientific landscape and ethical considerations pertinent to the ISSCR’s mission of advancing stem
cell science and its application to human disease.
Please email your feedback to info@isscr.org with the subject line “Comments on ISSCR
Guidelines.” We encourage you to use the provided feedback form or similar format to submit your
comments.
Comments are being accepted by email through 10 September, 2015.
Following this period of public comment, the Task Force will digest and discuss the feedback, and
make suitable revisions in anticipation of a public release of a final document in January of 2016.
While stem cell research offers great promise for the advancement of fundamental scientific
knowledge and the relief of human suffering, it merits careful scientific as well as ethical
deliberation, and compels constant vigilance so that scientific research and clinical practice is
conducted with proper review and reflection.
The ISSCR greatly values your input as we work towards finalizing these Guidelines.
Jonathan Kimmelman, Task Force Chair
George Q. Daley, ISSCR Board of Directors

2. 1
Guidelines for Stem Cell Science1
and Clinical Translation2
3
4
Draft June 26, 20155
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7
8
9

3. 2
Table of Contents1
1. Fundamental Ethical Principles...........................................................................................................32
2. Human Embryonic Stem Cell Research and Related Laboratory Research Activities ...53
2.1 Review Processes...............................................................................................................................54
2.2 Procurement of Biomaterials........................................................................................................95
2.3 Banking and Distribution of Human Pluripotent Stem Cell Lines ............................... 146
2.4 Mechanisms for Enforcement.................................................................................................... 177
3. Guidelines for Clinical Translation of Stem Cell-Based Research........................................ 188
3.1 Cell Processing and Manufacture ............................................................................................. 189
3.1.1 Sourcing Material ................................................................................................................... 1810
3.1.2 Manufacture ............................................................................................................................. 2011
3.2 Preclinical Studies .......................................................................................................................... 2212
3.2.1 General Considerations........................................................................................................ 2213
3.2.2 Animal Safety Studies ........................................................................................................... 2414
3.2.3 Animal Efficacy Studies........................................................................................................ 2615
3.2.4 Transparency and Publication .......................................................................................... 2816
3.3 Clinical Research............................................................................................................................. 2817
3.3.1 Oversight.................................................................................................................................... 2918
3.3.2 Standards for Ethical Conduct........................................................................................... 2919
3.3.3 Issues Particular to Early Phase Trials........................................................................... 3220
3.3.4 Issues Particular to Late Phase Trials ............................................................................ 3321
3.3.5 Research Subject Follow-Up and Trial Monitoring................................................... 3422
3.3.6 Stem Cell-Based Medical Innovation .............................................................................. 3523
3.3.7 Transparency and Reporting of Research Results .................................................... 3824
3.4 Clinical application......................................................................................................................... 3925
3.4.1 Issues in clinical use.............................................................................................................. 3926
3.4.2 Access and Economics.......................................................................................................... 4127
4. Public Communications....................................................................................................................... 4228
5. Standards in Stem Cell Research...................................................................................................... 4429
ISSCR GUIDELINES UPDATES TASK FORCE..................................................................................... 4630
APPENDICES................................................................................................................................................. 4731
REFERENCES................................................................................................................................................ 4832
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4. 3
1. Fundamental Ethical Principles1
2
The primary social mission of basic biomedical research and its clinical translation is to3
alleviate and prevent human suffering caused by illness and injury. All such biomedical4
research is a collective endeavor. It depends on the contributions of many kinds of5
individuals, including basic scientists, clinicians, patients, members of industry, advocates,6
governmental officials, and others. Such individuals often work across institutions,7
professions, and national boundaries, and are bound by different social and cultural beliefs,8
regulatory regimes, and expectations for moral conduct. Each may also be working toward9
different goals. When this collective effort works well, the social mission of clinical10
translation is achieved efficiently, alongside the private interests of its various contributors.11
12
Ethics principles and guidelines help secure the basis for this collective endeavor. Patients13
can enroll in clinical research trusting that studies are well justified and the risks and burdens14
reasonable in relation to potential benefits. Physicians and payers can be confident that the15
evidence they use to make important health care decisions is rigorous and unbiased. Private16
firms can invest in research programs knowing that public and institutional support will be17
forthcoming for the foreseeable future.18
19
The ISSCR guidelines pertain to human embryonic stem cell research and clinical20
translation, and are meant to promote an efficient, appropriate and sustainable research21
enterprise aimed at the development of stem cell-based interventions that will improve22
human health. The guidelines that follow build on a set of widely shared ethical principles in23
science(Banda, 2000; Institute of Medicine, 2009), research with human subjects, and24
medicine.(1949; Department of Health and Education and Welfare, 1979; Medicine et al.,25
2002; World Medical Association, 1964) Some of these guidelines would apply for any26
basic research and clinical translation efforts. Others respond to challenges that are27
especially applicable to stem cell-based research. These include sensitivities surrounding28
research that involves the use of human embryos and gametes; irreversible risks associated29
with some cell-based interventions; the vulnerability and pressing medical needs of patients30
with serious illnesses that currently lack effective treatments; public expectations about31
medical advance and access; and the competitiveness within this research arena.32
33
Integrity of the Research Enterprise34
The primary goals of stem cell-based research are to advance scientific understanding and to35
generate evidence for addressing unmet medical and public health needs. This research36
should be overseen by qualified investigators and coordinated in a manner that ensures that37
the information obtained will be trustworthy, reliable, accessible, and responsive to scientific38
uncertainties and priority health needs. Doing so entails the need for independent peer39
review, transparency, and continued monitoring at each stage of research.40
41
42
Respect for Human Research Participants43
Researchers, clinicians, and clinics should empower human subjects to exercise valid44
informed consent where they have adequate decision-making capacity. This means that45
patients—whether in research or care settings—should be offered accurate information about46

5. 4
risks and the state of evidence for novel stem cell-based strategies. Where individuals lack1
such capacity, surrogate consent should be obtained and subjects should be stringently2
protected from nontherapeutic risks exceeding minor increase over minimal. In addition to3
supporting the autonomy of human subjects, the principle of respect for research participants4
should also be interpreted broadly to include accommodating the conscientious objections of5
researchers or their support staff who may not ethically endorse every aspect of human stem6
cell research.7
8
Social Justice9
The benefits of clinical translation efforts should be distributed justly and globally, with10
particular emphasis on addressing the medical and public health needs for populations with11
the greatest unmet health needs. Advantaged populations should make particular efforts to12
share benefits with disadvantaged populations. Risks and burdens associated with clinical13
translation should not be borne by populations that are unlikely to benefit from the14
knowledge produced in these efforts. As much as possible, healthcare delivery systems,15
already overburdened by the rising cost of health care, should not bear the additional costs of16
proving the safety and efficacy of stem cell-based interventions. Instead, these should be17
absorbed by research and commercial entities, which are expressly privileged to profit from18
investing in new technology development. It is a matter of justice that the costs of uncertainty19
about clinical utility be minimized and reduced to an acceptable level before novel treatments20
are applied in healthcare systems. Where cell-based interventions are introduced into clinical21
application amid uncertainties, their application should be coupled to evidence development.22
23
Transparency24
Parties to the testing and application of stem cell-based interventions should promote timely25
exchange of accurate scientific information to other interested parties. Investigators should26
communicate with various publics, such as patient communities, to respond to their27
information needs, and should convey the scientific state of the art, including uncertainty28
about the utility of clinical applications. Research teams should promote open and prompt29
sharing of ideas, data and materials.30
31
Primacy of Patient Welfare32
Physicians and physician-researchers owe their primary duty to the patient and/or research33
subject. Clinical testing should never allow promise for future patients to override the welfare34
of current research subjects. Application of stem cell-based interventions outside of formal35
research settings should be evidence based, subject to independent expert review, and seek to36
serve the patients’ best interests. Promising innovative strategies should be systematically37
evaluated as early as possible, and before application in large populations. The marketing and38
provision of stem cell-based interventions to a large patient population prior to garnering39
endorsement of safety and efficacy through a process of rigorous and independent review by40
experts constitutes a breach of professional ethics, and unduly places vulnerable patients at41
risk.42

6. 5
2. Human Embryonic Stem Cell Research and Related Laboratory Research1
Activities2
3
The guidelines in this section pertain to the procurement, derivation, banking, distribution,4
and preclinical use of pluripotent cells taken from the earliest stages of human development;5
to the procurement of gametes and somatic cells for stem cell research; and to the in vitro and6
animal modeling uses of human totipotent or pluripotent cells or human pluripotent stem cell7
lines where the experiments raise particular concerns, as outlined in greater detail below.8
9
The guidelines articulated in this chapter are compatible in their potential application to10
various types of embryonic and fetal cells, embryonic germ cells derived from fetal tissue,11
and in vitro research on human embryos and gametes. Institutions and investigators12
conducting basic research with these human biomaterials should follow the guidelines insofar13
as they pertain to the three categories of research discussed below.14
15
2.1 Review Processes16
17
Oversight18
Recommendation 2.1.1: All human stem cell research that (1) involves pre-implantation19
stages of human development, human embryos or embryo-derived cells, (2) entails20
incorporating human totipotent or pluripotent cells into animal hosts to achieve a high21
degree of chimerism of either the central nervous system or germ line, or (3) entail the22
production of human gametes in vitro when such gametes are tested by fertilization or23
for the creation of embryos, shall be subject to review, approval, and ongoing24
monitoring by a stem cell research oversight (SCRO) process equipped to evaluate the25
unique aspects of the science. The derivation of pluripotent stem cells from somatic cells26
via genetic or chemical means of reprogramming does not require SCRO process27
review as long as the research does not generate human embryos or entail sensitive28
aspects of the research use of pluripotent stem cells as outlined herein.29
30
The stem cell research oversight (SCRO) process can be performed at the institutional, local,31
regional, national, or international level, or by some coordinated combination of those32
elements provided that the review as a whole occurs effectively, impartially and rigorously.33
Multi-institutional arrangements for coordinated review, which involve delegation of specific34
parts of this review, shall be permitted as long as they meet that standard. A single review35
rather than redundant review is preferable as long as the review is thorough and is capable of36
addressing any uniquely sensitive elements of human stem cell research. Unless the review is37
specifically designed to be comprehensive, the SCRO process shall not replace other38
mandated institutional reviews that assess the participation of human subjects in research, or39
the oversight for animal care, biosafety, or the like. Review should consider the protection of40
sensitive medical data of human biomaterials donors. Such a review is typically done by a41
local institutional review board or its equivalent, but could also be performed as part of the42
SCRO process, which must exercise due regard for the authority of the institutional review43
board and avoiding duplication of its functions.44
45

7. 6
Composition of SCRO process review committees1
Recommendation 2.1.2: SCRO Review committees executing the SCRO process should2
be comprised of scientists, ethicists, and community members who are not directly3
engaged in the research under consideration.4
5
Potential participants in the SCRO process should be selected based on their highly relevant6
area-specific scientific and/or clinical expertise, capacity for impartiality, and freedom from7
political or financial conflict regarding the research to be evaluated. Those responsible for8
formulating the mechanism or body to provide SCRO function must be cognizant of the9
potential for conflicts of interest both financial and non-financial that might compromise the10
integrity of the review process, and attempt to minimize or eliminate such conflicts.11
12
Review Categories13
Recommendation 2.1.3: To ensure that stem cell research is proceeding with due14
consideration, to ensure consistency of research practices among scientists globally and15
to specify the nature of scientific projects that should be subject to review, SCRO16
process review committees or their equivalents should utilize the following three17
categories of research.18
19
2.1.3.1 Category 1 (Exempt From Full SCRO Process Review): Research that is permissible20
after review under existing mandates and by existing committees, and is determined to be21
exempt from full SCRO process review. Category 1 research includes the following22
activities:23
24
a) Research with pre-existing human embryo-derived stem cell lines that are confined25
to cell culture or involve routine and standard research practice, such as assays of in26
vitro differentiation or teratoma formation in immune-deficient mice;27
28
b) Research that entails the reprogramming of somatic cells to pluripotency without29
the creation of embryos or totipotent cells (e.g., generation of induced pluripotent30
stem cells).31
32
These guidelines recommend that all institutions pursuing Category 1 research establish an33
administrative mechanism capable of determining that a) these projects can be adequately34
reviewed by committees with jurisdiction over research on human tissues, animals, biosafety,35
radiation, etc. and b) that full SCRO process review by a SCRO mechanism or body is not36
required. This administrative mechanism should include a determination that the provenance37
of the human embryo-derived stem cell lines to be used has been scrutinized and deemed38
acceptable according to the principles outlined in this document, and that such research is in39
compliance with scientific, legal and ethical norms.40
41
2.1.3.2 Category 2 (Full SCRO Process Review): Forms of research that are permissible only42
after full SCRO process review to address the issues pertinent to human pluripotent stem cell43
research. Full review should be coordinated with other relevant oversight, such as that44
provided by human subjects review boards or in vitro fertility clinical oversight bodies.45
Forms of research requiring full review include the following activities:46
47

8. 7
a) Research involving the derivation of new human pluripotent cell lines from human1
embryos or discarded fetal tissues. This includes the creation of human embryos or2
embryo-like structures expressly for stem cell research purposes (subject to applicable3
local laws), regardless of how the embryos are created. SCRO process review should4
consider the scientific justification for the creation and use of research embryos,5
including, but not limited to, the importance of the research question at hand and the lack6
of suitable alternative means to investigate this question.7
8
b) Research in which human pluripotent stem cells derived by any means are used to9
generate human totipotent cells that are defined as having the potential to sustain10
embryonic or fetal development;11
12
c) Research that generates human gametes and entails performing studies of fertilization13
that produce human embryos;14
15
d) Research in which human totipotent cells or pluripotent stem cells derived by any16
means are mixed with pre-implantation human embryos. In no case shall such17
experiments be sustained beyond initiation of primitive streak formation.18
19
e) Forms of research that generate chimeric animals using human cells that have the20
potential for high degrees of functional integration into the animals’ central nervous21
systems or to generate human gametes. To assist SCRO process review of stem cell-22
based human-to-nonhuman chimera research, the ISSCR Ethics and Public Policy23
Committee has provided an advisory report that guides reviewers through a series of24
considerations not typically covered by institutional animal research committees but that25
are relevant for SCRO review (Appendix 6). SCRO reviewers and investigators should26
follow the proposed ethical standards presented in this report, while exercising27
appropriate judgment in individual situations.28
29
f) Institutions should determine whether chimera research involving human neural cells30
that have the capacity to integrate into the nervous systems of laboratory animals should31
be reviewed by either the SCRO or animal research review process. Such evaluations32
should be triggered when the degree of functional integration is considerable enough to33
raise concerns that the nature of the animal host may be substantially altered, and34
especially when transplants occur in closely related primate species. Review by animal35
care and use committees should be supplemented by scientists and ethicists with relevant36
topic-specific expertise.37
38
2.1.3.3 Category 3 (Prohibited Activities): Research that should not be pursued at this time39
because of broad international consensus that such experiments lack a compelling scientific40
rationale or raise substantial ethical concerns. Such forms of research include the following:41
42
a) In vitro culture of any intact human embryo or organized cellular structures that might43
manifest human organismal potential, regardless of derivation method, for longer than 1444
days or until formation of the primitive streak begins, whichever occurs first.45
46

9. 8
b) Research in which human embryos or any products of research involving human1
totipotent or pluripotent cells are implanted into a human or non-human primate uterus.2
3
c) Research in which gene-edited human embryos are implanted into a human or non-4
human primate uterus. Gene-edited human embryos are defined as human embryos with5
in vitro modifications to their nuclear DNA and/or embryos generated from a human6
gamete that has had its nuclear DNA modified in vitro. (For guidance on clinical7
applications of human genome editing, see below.)8
9
d) Research in which animal chimeras incorporating human cells with the potential to10
form human gametes are bred to each other.11
12
Related Laboratory Research Activities13
Research involving the in vitro genetic manipulation of human embryos and gametes is14
rapidly advancing internationally. Such experiments may inform mechanisms of early15
human development, or lay the foundation for eradication of genetic disease. Two prominent16
examples of this are (1) novel strategies to manipulate mitochondrial content of human17
oocytes or embryos, and (2) human nuclear genome editing techniques, most notably the use18
of the CRISPR/Cas9 system. Either of these examples might one day help prevent the19
transmission of serious genetic diseases while allowing prospective parents to maintain a20
genetic link to their offspring.21
22
Preclinical research into the safety and efficacy of mitochondrial replacement strategies is23
now underway and should continue under appropriate regulatory oversight. Mitochondrial24
replacement therapy does not entail direct modification to the nuclear genome, depends upon25
distinct technologies, and raises unique scientific and ethical concerns. Thoughtful scientific and26
ethical discussions of this technology have recently occurred in the United Kingdom and are27
underway in the United States and elsewhere in the world. The ISSCR applauds these current28
efforts as a model for deliberations on germline nuclear genome editing technologies. Nuclear29
genome editing techniques applied to the human germline are far less developed at this time,30
and raise additional technological and societal challenges. Scientists currently lack an31
adequate understanding of the fidelity and precision of CRISPR/Cas9 genome modification32
of human embryos, as well as a full appreciation of the safety and potential long-term risks to33
individuals born following such a process. As of the issuance of these guidelines, the ISSCR34
supports only in vitro laboratory research on applications of nuclear genome editing35
technologies to human embryos, performed under proper ethical oversight, to enhance basic36
knowledge and to better understand the associated safety issues. ISSCR also calls for broad37
public and international dialogue on the capabilities and limitations of these genome-editing38
technologies and on the implications of their application to the human germ line. The ISSCR39
asserts that a deeper and more rigorous deliberation on the ethical, legal and societal40
implications of modifying the human germ line is essential if clinical application is ever to be41
sanctioned.42
43
Recommendation 2.1.4: Basic research on the safety and efficacy of modifying gametes44
and/or pre-implantation human embryos is essential prior to their use in clinical45
investigation of assisted reproductive strategies aimed at preventing the transmission of46
genetic disorders. Until further clarity emerges on both scientific and ethical fronts, the47

10. 9
ISSCR supports a moratorium on attempts to apply CRISPR/Cas9 and other nuclear1
genome editing techniques to human embryos for the purpose of human reproduction.2
3
2.2 Procurement of Biomaterials4
5
The procurement of human gametes, embryos in vitro, fetal tissues, and somatic cells are6
integral to the conduct of human stem cell research. The international community of7
professional scientists conducting human stem cell research must ensure that human8
biological materials are procured in a manner according to globally accepted principles of9
research ethics and local laws and regulations.10
11
Oversight of Procurement12
Recommendation 2.2.1: Rigorous review must be performed prior to the procurement13
of all gametes, embryos, or somatic cells that are destined for use in research.14
Normally, human subjects review committees are responsible for conducting this15
review, although SCRO process review may assist by providing stem cell-specific16
expertise.17
18
Review must ensure that vulnerable populations are not exploited due to their dependent19
status or their compromised ability to offer voluntary consent, and that there are no undue20
inducements or other undue influences for the provision of human biomaterials.21
22
Consent for Biomaterials23
Recommendation 2.2.2: Explicit and contemporaneous informed consent for the24
provision of all biomaterials for stem cell research is ideal, including consent obtained25
from all gamete donors for use of embryos in research. Informed consent should be26
obtained at the time of proposed transfer of any biomaterials to the research team or27
during the time that biomaterials are collected and stored for future research use.28
29
Explicit consent must also be given for discarded tissues and cells collected during the course30
of clinical practice if these biomaterials are used for stem cell research involving the creation31
of human embryos (e.g., by somatic cell nuclear transfer or another method that reprograms32
to totipotency).33
34
Contemporaneous consent is not necessary if researchers procure somatic cells from a tissue35
bank. However, somatic cells may be procured from a tissue bank only if the tissue bank’s36
informed consent documents specifically designate embryo or gamete creation for stem cell37
research as one of the possible uses of the donor’s tissues, and only if researchers use somatic38
cells from tissue samples whose donors have clearly consented to this possible use.39
40
In the case that human biomaterials are procured from a child or a decisionally incapacitated41
adult, consent must be provided by a parent, legal guardian or other person authorized under42
applicable law. Assent of the minor is also strongly encouraged.43
44
Review for Biomaterials Collection for Research45

11. 10
Recommendation 2.2.3: Reviews of procurement protocols must ensure that1
biomaterials donors are adequately informed about the stem cell-specific aspects of2
their voluntary research participation.3
4
Researchers should exercise care in obtaining valid informed consent. The informed consent5
process should take into account language barriers and the educational level of the6
participants themselves. In order to facilitate the adoption of sound and uniform standards of7
informed consent for the procurement of biomaterials for human stem cell research, the8
ISSCR has made sample documents available to researchers by download from its9
website.(Isscr.org, 2015) The samples will need to be customized for use in specific research10
studies and to conform to local laws.11
12
The informed consent document and process should cover the following statements (adapted13
to the particular research project):14
15
i. that the biomaterials will be used in the derivation of totipotent or pluripotent16
cells for research;17
ii. that the biomaterials will be destroyed during the process of deriving18
totipotent or pluripotent cells for research;19
iii. that derived cells and/or cell lines might be deposited and stored in a20
repository many years and used internationally for future studies, many of21
which may not be anticipated at this time;22
iv. that cells and/or cell lines might be used in research involving genetic23
manipulation of the cells, the generation of human-animal chimeras (resulting24
from the mixing of human and non-human cells in animal models), or the25
introduction of cells or their derivatives into human or animal embryos;26
v. that the donation is made without any restriction or direction regarding who27
may be the recipient of transplants of the cells derived, except in the case of28
autologous transplantation;29
vi. whether the donation is limited to specific research purposes and not others or30
is for broadly stated purposes, including research not presently anticipated, in31
which case the consent shall notify donors, if applicable under governing law,32
of the possibility that permission for broader uses may later be granted and33
consent waived under appropriate circumstances by an ethical or institutional34
review board. The consent process should explore and document whether35
donors have objections to the specific forms of research outlined in the36
research protocol;37
vii. disclosure of what donor medical or other information and what donor38
identifiers will be retained; specific steps taken to protect donor privacy and39
the confidentiality of retained information; and whether the identity of the40
donor will be readily ascertainable to those who derive or work with the41
resulting stem cell lines, or any other entity or person, including specifically42
any oversight bodies and government agencies;43
viii. disclosure of the possibility that any resulting cells or cell lines may have44
commercial potential, and whether the donor will or will not receive financial45
benefits from any future commercial development;46

12. 11
ix. disclosure of any present or potential future financial benefits to the1
investigator and the institution related to or arising from proposed research;2
x. that the research is not intended to provide direct medical benefit to anyone3
including the donor, except in the sense that research advances may benefit4
the community;5
xi. that neither consenting nor refusing to donate biomaterials for research will6
affect the quality of care provided to potential donors;7
xii. that there are alternatives to donating human biomaterials for research, and an8
explanation of what these alternatives are;9
xiii. (for donation of embryos) that the embryos will not be used to attempt to10
produce a pregnancy, and will not be allowed to develop in culture in vitro for11
longer than 14 days from conception;12
xiv. (for experiments in embryonic stem cell derivation, somatic cell nuclear13
transfer, somatic cell reprogramming, parthenogenesis, or androgenesis) that14
the resulting cells or stem cell lines derived would carry some or all of the15
DNA of the donor and therefore be partially or completely genetically16
matched to the donor.;17
xv. that nucleic acid sequencing of the resulting stem cell line is likely to be18
performed, and data stored in databases available to the public or to qualified19
researchers with confidentiality provisions; this may compromise the capacity20
for donation to remain anonymous and/or de-identified;21
xvi. whether there is a plan to share with the biomaterials donor any clinically22
relevant health information discovered incidentally during the course of23
research.24
25
Payments to tissue providers for research26
Recommendation 2.2.4: Research oversight committees must authorize all proposals to27
reimburse, compensate, or provide valuable considerations of any kind for research28
providers of embryos, gametes, or somatic cells.29
30
Individuals who elect to provide stored embryos, gametes, or somatic cells for research31
should not be reimbursed for the costs of storage prior to the decision to participate in32
research.33
34
For provision of somatic cells, sperm, or oocytes for research, reimbursement for direct35
expenses incurred by donors as a consequence of research participation may be determined36
during the review process.37
38
For provision of fetal tissue after an elective abortion, no payment or valuable consideration39
of any kind may be offered to donors for their procurement.40
41
Payments to oocyte providers for research42
Recommendation 2.2.5: For provision of oocytes for research, when oocytes are43
collected outside the course of clinical treatment, at no time should compensation for44
non-financial burdens ever constitute an undue inducement.45
46

13. 12
In jurisdictions where oocyte provision for research is allowed, the human subjects1
committee (IRB/ERB) and those responsible for conducting rigorous SCRO review must2
assess the safety and the voluntary and informed choice of oocyte providers according to the3
following standards:4
5
i. There must be monitoring of recruitment practices to ensure that no vulnerable6
individuals, for example, economically disadvantaged women, are7
disproportionately encouraged to participate as oocyte providers for research.8
ii. In jurisdictions where research participants are allowed compensation or9
valuable consideration for incurred non-financial burdens, the amount of10
financial recognition for the participant’s time, effort, and inconvenience must11
be rigorously reviewed to ensure that such compensation does not constitute an12
undue inducement.13
iii. Compensation for oocyte providers’ time, effort, and inconvenience, if14
permitted by local review committees, should be reasonably proportionate to15
recompense levels for other types of research participation involving similarly16
invasive and burdensome medical procedures. Compensation levels should aim17
to acknowledge oocyte providers’ non-financial burdens incurred as a result of18
their research participation, such as their physical discomfort and effort.19
iv. At no time should payments or other rewards of any kind be given for the20
number or quality of the oocytes that are to be provided for research.21
v. To help guide review committees through the ethical considerations surrounding22
oocyte collection and financial recognition of donors’ efforts, the ISSCR Ethics23
and Public Policy Committee has produced a white paper explaining the24
ISSCR’s position on these issues. Researchers and review committees should25
consult Appendix 1 for further guidance.26
vi. Oocyte procurement must be performed only by medically qualified and27
experienced physicians, and non-aggressive hormone stimulation cycles and28
frequent monitoring must be used to reduce the risk of ovarian hyperstimulation29
syndrome (OHSS).30
vii. Due to the unknown long-term effects of ovulation induction, women should31
not undergo an excessive number of hormonally induced ovarian stimulation32
cycles in a lifetime, regardless of whether they are induced for research or33
assisted reproduction. The limits should be determined by thoughtful review34
during the SCRO process, which should be informed by the latest available35
scientific information about the health risks.36
viii. There should be a provision for the research institution or funding source to pay37
for the cost of any medical care required as a direct and proximate result of a38
woman’s provision of oocytes for research.39
ix. A fertility clinic or other third party responsible for obtaining consent or40
collecting biomaterials should not be paid specifically for the material obtained,41
but rather for specifically defined cost-based reimbursements and payments for42
professional services.43
44
Separating Research Donation Consent from Treatment45

14. 13
Recommendation 2.2.6: Informed consent for research donation must be kept separate1
from informed consent for clinical treatment.2
3
To facilitate free and voluntary choice, decisions related to the donation of gametes or4
creation of embryos for fertility treatment should be free of the influence of investigators5
who propose to derive or use human pluripotent stem cells in research. During the course of6
clinical treatment, researchers may not request that members of the fertility treatment team7
generate more embryos or harvest more oocytes than necessary for the optimal fertility8
treatment. Wherever possible, the treating physician or infertility clinician should not also be9
the investigator who is proposing to perform research on the donated materials.10
11
Consistent with fetal tissue research guidelines issued by the Network of European NCS12
Transplantation and Restoration (NECTAR) and U.S. law, a woman’s decision to terminate a13
pregnancy must not be influenced by the possible research use of her fetus’ tissues. Informed14
consent for fetal tissue procurement and research should be obtained from the woman after15
her clinical decision to terminate her pregnancy but before the abortive procedure.16
17
Improving Informed Consent for Donation18
Recommendation 2.2.7: Attempts should be made to improve the informed consent19
process and study design of human biomaterials procurement.20
21
The informed consent document is but one aspect of this process. The purpose of the22
informed consent document is to record that all the ethically relevant information has been23
discussed. The informed consent document alone can never take the place of a dialogue24
between research staff and providers of human biomaterials. Researchers are thus encouraged25
to focus on enriching the informed consent process itself, in addition to improving the design26
of the protocol with respect to procurement. These processes can be enhanced in the27
following ways:28
29
i. Whenever possible, the person conducting the informed consent dialogue30
should have no vested interest in the research protocol. If members of the31
research team participate in the informed consent process, their role must be32
disclosed and care must be taken to ensure that information is provided in a33
transparent and accurate manner.34
ii. Empirical research has shown that informed consent is most effective as a35
dynamic, interactive, and evolving process as opposed to a static, one-time36
disclosure event.(Flory and Emanuel, 2004) Thus, researchers should provide37
ample opportunities for biomaterials donors to discuss their involvement in38
the research protocol.39
iii. Counseling services should be made available upon request to any providers40
of human biomaterials prior to procurement.41
iv. Procurement procedures should be revised in light of a) ongoing studies of the42
long-term risks associated with oocyte retrieval; and b) research on informed43
consent for all types of human biological materials procurement.44
v. Researchers should consider on a regular basis, subject to annual review, the45
possible use of alternatives to hormonally induced oocytes procured solely for46

15. 14
stem cell research, such as oocytes derived from pluripotent stem cells, in1
vitro maturation of oocytes from ovariectomy samples, and egg sharing2
programs offered through infertility clinics.3
2.3 Banking and Distribution of Human Pluripotent Stem Cell Lines4
5
Proposals for derivations of new human pluripotent stem cell lines should be scientifically6
justified and executed by scientists with appropriate expertise. Hand-in-hand with the7
privilege to perform derivations is the obligation to distribute the cell lines to the research8
community.9
10
Banking in Derivation Protocols11
Recommendation 2.3.1: A clear, detailed outline for banking and open access to the new12
lines should be incorporated into derivation proposals. New pluripotent stem cell lines13
should be made generally available as soon as possible following derivation and first14
publication.15
16
Consistent with the policies of many funders and scientific journals, the ISSCR encourages17
researchers to deposit lines early into centralized repositories where the lines will be held for18
release and distribution upon publication. Investigators performing derivations should have a19
detailed, documented plan for characterization, storage, banking and distribution of new20
lines. Investigators performing derivations should propose a plan to safeguard the privacy of21
donors and for managing their health-related incidental findings. Investigators should also22
inform donors that, in this era of data-intensive research, complete privacy protection might23
be difficult to guarantee.24
25
During the course of primary or secondary research with human stem cell lines, particularly26
lines derived from somatic cells, investigators may discover information that may be of27
importance to biomaterials donors. Therefore, investigators and stem cell repositories should28
develop policies to address these possibilities.29
30
Incidental Findings31
Recommendation 2.3.2: Primary researchers and repositories should develop a policy32
that states whether or not incidental findings will be returned to study participants.33
This policy must be explained to potential participants during the informed consent34
process, and participants should be able to choose which types of incidental findings35
they wish to receive, if any. Reporting findings with relevance to public health may be36
required by law in certain jurisdictions.37
38
Because it is presently unclear what the net harms and benefits are of returning incidental39
findings to biomaterials donors, a single approach to managing incidental findings may not40
be appropriate across all studies and jurisdictions.41
42
Nevertheless, in the case that there are plans to return incidental findings to research43
participants, primary researchers must offer a practical and adequately resourced feedback44
pathway to participants who desire such information that involves participants’ physicians45
and the verification of any discovered incidental findings.46

16. 15
1
Secondary researchers should be aware that they are typically prohibited from attempting to2
contact or reidentify donors with incidental findings information. Recontact is a matter for3
primary research sites or central repositories to manage. Secondary researchers however4
should be aware of the incidental findings policies of either of these responsible parties.5
6
Central repositories should adhere to the incidental findings policies of primary researchers7
or others collecting biomaterials from donors that were disclosed during the informed8
consent process and which produced the samples stored at the repository.9
10
Repositories11
Recommendation 2.3.3: The ISSCR encourages the establishment of national and12
international repositories, which are expected to accept deposits of newly derived stem13
cell lines and to distribute them on an international scale.14
15
In order to facilitate easy exchange and dissemination of stem cell lines, repositories should16
strive to form and adhere to common methods and standards (see also chapter 5). At a17
minimum, each repository must establish its own guidelines and make those available to the18
public. Repositories must have a clear, easily accessible material transfer agreement (MTA; a19
sample MTA is available in Appendix 2). Each repository may have its own criteria for20
distribution. The repository has right of refusal if a cell line does not meet its standards.21
22
Repositories must also have clear, publicly available protocols for deposit, storage and23
distribution of pluripotent stem cell lines and related materials.24
25
For deposits, repositories must receive documentation pertinent to the depositor’s applicable26
SCRO process. These documents should be kept on file at the repository. This will include,27
but is not limited to, proof of institutional and/or SCRO approval of the process for28
procurement of research materials according to ethical and legal principles of procurement as29
outlined in these Guidelines, approval of protocols for derivation of new lines, copies of the30
donor informed consent documents and what, if any, reimbursement of direct expenses or31
financial considerations of any kind were provided to the donors.32
33
Repositories should obtain all technical information from depositor. For example, methods34
used in the derivation of lines, culture conditions, infectious disease testing, passage number35
and characterization data. Repositories will make this information publicly available. If the36
repository modifies depositor’s protocols or obtains additional data this will also be made37
available.38
39
Repositories should engage in, but are not limited to, the following:40
i. Reviewing and accepting deposit applications;41
ii. Assigning unique identifiers (catalogue number) to deposits;42
iii. Characterizing cell lines;43
iv. Human pathogen testing;44
v. Expansion, maintenance and storage of cell lines;45
vi. Quality assurance and quality control of all procedures;46

17. 16
vii. Maintenance of website with pertinent characterization data, protocols and1
availability of cell lines;2
viii. Tracking distributed cell lines;3
ix. Posting a clear and fair cost schedule for distribution of materials.4
Repositories should distribute internationally and charge only the necessary5
costs, which include shipping and handling;6
x. Adhering to an action plan (as applicable) for the return of incidental health7
related findings to donors.8
9
Provenance of Stem Cell Lines10
Recommendation 2.3.4: Documentation of the provenance of the stem cell lines is11
critical if the cell lines are to be widely employed in the research community.12
Provenance must be easily verifiable by access to relevant informed consent documents13
and raw primary data regarding genomic and functional characterization.14
15
Owing to the nature of the materials involved in the generation of human stem cell lines,16
appropriate safeguards should be used to protect the privacy of donors and donor17
information. In order for the stem cell lines to be as useful as possible and so as not to18
preclude future potential therapeutic applications, as much donor information as possible19
should be maintained along with the cell line, including, but not limited to: ethnic20
background, medical history, and infectious disease screening. Subject to local laws, donor21
samples and cell lines should be anonymized or de-identified using internationally accepted22
standards for maintaining privacy. Informed consent and donor information will be gathered23
and maintained by the repository, including whatever reimbursement of direct expenses or24
financial or valuable considerations of any kind were provided in the course of the25
procurement.26
27
Access to Research Materials28
Recommendation 2.3.5: Institutions engaged in human stem cell research, whether29
public or private, academic or otherwise, should develop procedures whereby research30
scientists are granted, without undue financial constraints or bureaucratic impediment,31
unhindered access to these research materials for scientifically sound and ethical32
purposes, as determined under these guidelines and applicable laws.33
34
The ISSCR urges such institutions, when arranging for disposition of intellectual property to35
commercial entities, to make best efforts to preserve nonexclusive access for the research36
community, and to promote public benefit as their primary objective. The ISSCR endorses37
the principle that as a prerequisite for being granted the privilege of engaging in human stem38
cell research, researchers must agree to make the materials readily accessible to the39
biomedical research community for non-commercial research. Administrative costs such as40
shipping and handling should be borne by the receiving party so as not to pose an undue41
financial burden on the entity or researcher providing the cells.42
43
The ISSCR encourages scientists conducting human stem cell research to submit any human44
stem cell lines they derive to national or international depositories that allow open45
distribution in order to facilitate the wider dissemination of these valuable research tools46

18. 17
across national boundaries. Scientists and stem cell bio-banks should work together to1
harmonize standard operating procedures to facilitate international collaboration (see chapter2
5).3
2.4 Mechanisms for Enforcement4
5
Recommendation 2.4.1: These ISSCR guidelines should be upheld and enforced6
through standards of professional and institutional self-regulation.7
8
The development of consensus in ethical standards and practices in human stem cell research9
through thoughtful and transparent dialogue is a critical catalyst for international10
collaboration to proceed with confidence, and for research from anywhere in the world to be11
accepted as valid by the scientific community. These standards and practices should be12
incorporated in a comprehensive code of conduct applicable to all researchers in the field.13
Senior or corresponding authors of scientific publications should specifically be charged with14
the responsibility of ensuring that the code of conduct is adhered to in the course of15
conducting human stem cell research and of supervising junior investigators that work in16
their respective organizations or projects. Institutions where such research is undertaken shall17
strive to provide to researchers working on any such projects under their auspices,18
particularly junior investigators, with up-to-date information on such standards and practices19
on an ongoing basis.20
21
Journal editors and manuscript reviewers should require an authors’ statement of adherence22
to the ISSCR ‘Guidelines for Human Embryonic Stem Cell Research and Related Laboratory23
Research Activities’ or adherence to an equivalent set of guidelines or applicable regulations,24
and authors should include a statement that the research was performed after obtaining25
approvals following a suitable SCRO review process.26
27
Grant applicants, in particular the individual scientists undertaking the research, should28
provide funding bodies with sufficient documentation to demonstrate that proposed research29
is ethically and legally in accordance with relevant local and national regulations and also in30
accordance with the ISSCR ‘Guidelines for the Human Embryonic Stem Cell Research and31
Related Laboratory Research Activities’. Funding organizations should pledge to follow32
these Guidelines or their equivalent and require entities whose research is funded by such33
organizations to do the same.34
35
In order to facilitate the adoption of globally-accepted standards and practice of human stem36
cell research, the ISSCR has made available for download examples of informed consent37
documents for obtaining human materials for stem cell research (gametes, embryos, somatic38
tissues), and a Material Transfer Agreement for the sharing and distribution of materials (see39
Appendices 2 and 3). These informed consent templates may be modified to comply with40
local laws. See also chapter 5.41
42
43
44
45
46

19. 18
3. Guidelines for Clinical Translation of Stem Cell-Based Research1
2
The rapid advances in basic stem cell research and the many reports of successful cell-based3
interventions in animal models of human disease have created high expectations for the4
promise of regenerative medicine and cell therapies. Accompanying the enormous attention5
paid by the media and the public to cellular therapies is the potentially problematic trend6
towards premature initiation of clinical application and trials, far in advance of what is7
warranted by sound, rigorous, and dispassionately assessed pre-clinical evidence. Clinical8
experimentation is expensive and burdensome for research subjects. Investing in a novel9
mode of medical intervention before there is a sound rationale, a plausible mechanism, and a10
high probability of success squanders scant resources and needlessly exposes research11
subjects to risk. This section advocates for a step-wise, prudent, and evidence-based advance12
towards clinical translation. By adhering to a commonly accepted and robust set of practice13
guidelines, stem cell science is best positioned to fulfill its potential.14
15
3.1 Cell Processing and Manufacture16
17
In most countries and jurisdictions, the use of cellular products for medical therapy is18
regulated by governmental agencies to ensure the protection of patients and the prudent use19
of resources so that novel therapies will be the most widely beneficial for the population.20
Although some cell and stem cell based products have now been approved for use in humans,21
a growing number of novel cellular products are being tested for myriad disease indications,22
and present new challenges in their processing, manufacture, and pathways for regulatory23
approval. Given the variety of potential cell products, these Guidelines emphasize that cell24
processing and manufacture of any product be conducted with scrupulous, expert, and25
independent review and oversight, to ensure as much as possible the integrity, function, and26
safety of cells destined for use in patients. Even minimal manipulation of cells outside the27
human body introduces risk of contamination with pathogens, and prolonged passage in cell28
culture carries the potential for genomic and epigenetic instabilities that could lead to29
deranged cell function or frank malignancy. While many countries have established30
regulations that govern the transfer of cells into patients (Appendix 4), optimized standard31
operating procedures for cell processing, protocols for characterization, and criteria for32
release remain to be refined for novel derivatives of pluripotent cells and many attendant cell33
therapies.34
35
Given the unique proliferative and regenerative nature of stem cells and their progeny and the36
uncertainties inherent in the use of this therapeutic modality, stem cell-based therapies37
present regulatory authorities with unique challenges that may not have been anticipated38
within existing regulations. The following recommendations involve general considerations39
for cell processing and manufacture. Technical details pertaining to cell sourcing,40
manufacture, standardization, storage, and tracking can be found in Appendix 5.41
3.1.1 Sourcing Material42
Donor Consent43
Recommendation 3.1.1.1: In the case of donation for allogeneic use, the donor should44
give written and legally valid informed consent that covers, where applicable, issues45

20. 19
such as terms for potential research and therapeutic uses, incidental findings, potential1
for commercial application, and other issues as described below.2
3
Researchers should ensure that subjects (or their surrogate decision-makers) adequately4
understand the following:5
a) the tissue itself and the cell lines and/or differentiated progenitors may be subject to6
storage. If possible, duration of storage should be specified;7
b) that the donor may (or may not) be approached in the future to seek additional8
consent for new uses, or to request additional material (blood or other clinical9
samples) or information;10
c) that the donor will be screened for infectious and possibly genetic diseases;11
d) that the donated cells may be subject to genetic modification by the investigator;12
e) that with the exception of directed donation, the donation is made without restrictions13
regarding the choice of the recipient of the transplanted cells;14
f) disclosure of medical and other relevant information that will be retained, and the15
specific steps that will be taken to protect donor privacy and confidentiality of16
retained information, including the date at which donor information will be17
destroyed, if applicable;18
g) the donor should be informed that in the case of pluripotent stem cells the ability to19
destroy all samples may be limited and that with newer genetic techniques complete20
anonymity may not be feasible21
h) the intent of donor must be ascertained should medically relevant information of the22
donor be discovered in the course of research (see sections 2.2.3 and 2.3.2 for a23
discussion of incidental findings)24
i) explanation of what types of genomic analyses (if any) will be performed and how25
genomic information will be handled; and26
j) disclosure that any resulting cells, lines or other stem cell-derived products may27
have commercial potential, and whether any commercial and intellectual property28
rights will reside with the institution conducting the research.29
The initial procurement of tissue from a human donor may or may not require Good30
Manufacturing Practice (GMP) certification, depending on the jurisdiction (Appendix 4), but31
should always be conducted using GLP (good laboratory practices). It should also follow32
regulatory guidelines related to human tissue procurement and maintain universal precautions33
to minimize the risks of contamination, infection, and pathogen transmission.34
35
36

21. 20
Donor Screening1
Recommendation 3.1.1.2: Donors must be screened for infectious diseases and other2
risk factors, as is done for blood and solid organ donation, and for genetic diseases as3
appropriate.4
5
Tissue procurement for generating pluripotent cells is similar to procurement of cells for6
other purposes and should be governed by the same rules and regulations. However, an7
important distinction between tissue donation and pluripotent stem cell generation that raises8
the stakes of screening is that, whereas tissues are distributed to a limited number of9
recipients, iPSC or other pluripotent-derived allogeneic tissues can potentially be implanted10
in large populations. In addition, cells are likely to be expanded in culture and/or exposed to11
xeno culture material prior to transplantation. As such the risks of transmission of12
xenoviruses and other infectious agents such as prion particles is proportionately greater.13
Scrupulous adherence to regulations and tracking of cells and the development of a risk14
mitigation plan is crucial to translation and uptake of cell based therapies. Regulatory15
agencies such as the US Food and Drug Administration and the European Medicines Agency16
have issued guidance regarding donor testing.(Food and Drug Administration, 2007; The17
Committee for Medicinal Products for Human Use (CHMP), 2007)18
3.1.2 Manufacture19
Quality Control in Manufacture20
Recommendation 3.1.2.1: All reagents should be subject to quality control systems to21
ensure the quality of the reagents prior to introduction into manufacturing. For22
extensively manipulated stem cells intended for clinical application, GMP procedures23
should be strictly followed.24
25
The variety of distinct cell types, tissue sources, and modes of manufacture and use26
necessitate individualized approaches to cell processing and manufacture. (For an expanded27
discussion of the manufacturing process, see Appendix 5.) The maintenance of cells in28
culture for any period of time places different selective pressures on the cells than when they29
exist in vivo. Cells in culture age and may accumulate both genetic and epigenetic changes,30
as well as changes in differentiation behavior and function. Scientific understanding of31
genomic stability during cell culture is primitive at best and assays of genetic and epigenetic32
status of cultured cells are still evolving. The guidance documents from the US FDA and33
European Medicines Agency cited above provide a roadmap for manufacture and quality34
control of cellular products, but given that many cellular products developed in the future35
will represent entirely novel entities with difficult-to-predict behaviors, scientists must work36
side-by-side with regulators to ensure that the latest information is available to inform the37
regulatory process. An important goal is the development of universal standards to enable38
comparisons of cellular identity and potency, which are critical for comparing studies and39
ensuring reliability of dose-response relationships and assessments of mechanisms of40
toxicity.41
42
Processing and Manufacture Oversight43
Recommendation 3.1.2.2: The degree of oversight and review of cell processing and44
manufacture in protocols should be proportionate to the risk induced by manipulation45

22. 21
of the cells, their source, the trial, and the number of research subjects who will be1
exposed to them.2
3
Pluripotent stem cells—regardless of particular cell type—carry additional risks due to their4
pluripotency. These include the ability to acquire mutations when maintained for prolonged5
periods in culture, to grow and differentiate into inappropriate cellular phenotypes, to form6
benign teratomas or malignant outgrowths, and to fail to mature. These confer additional risk7
to patients/subjects, and appropriate tests must be devised to ensure safety of stem cell8
derived products.9
10
Factors that confer greater risk to patient/subjects from cells include their differentiation11
potential, source (autologous, allogeneic), type of genetic manipulation (if any), homologous12
versus non-homologous or ectopic use, their persistence in the patient/subject, level of13
species specificity for cell type, and the integration of cells into tissues or organs (versus, for14
example, encapsulation).15
16
When adequate cellular material is available, assays that should be applied include global and17
comprehensive assessments of genetic, epigenetic, and functional assays, as judged by18
rigorous review by a panel of independent experts. For cryopreserved or otherwise stored19
products, any impact of short or long-term storage on product potency must be determined.20
While some practitioners claim freedom to practice the use of cell therapies as long as the21
cells are subject to only minimal manipulation, the onus rests on the practitioner to invite22
scrutiny over their process of cell manipulation, such that independent, disinterested experts23
can determine the proper level of regulatory oversight. Recent draft guidance provided by the24
FDA for public comment represents a thoughtful and cogent set of principles to delineate25
when manipulation of autologous cell-based products can no longer be considered minimal26
and must therefore be subject to FDA oversight.(Food and Drug Administration, 2014)27
28
In general, the stringency of review for cell processing and manufacture should increase as29
cells are tested in later phase studies, used in practice settings, or administered to multiple30
recipients.31
32
Components of Animal Origin33
Recommendation 3.1.2.3: Components of animal origin used in the culture or34
preservation of cells should be replaced with human or chemically defined components35
when possible.36
37
Components of animal origin present risk of transferring pathogens or unwanted biological38
material. In some circumstances, it may not be possible or optimal to follow this39
recommendation. Researchers can rebut this presumption by demonstrating the infeasibility40
of alternatives, and the favorability of risk/benefit in spite of using animal-based components.41
42
Databases43
Recommendation 3.1.2.4: Funding bodies, industry, and regulators should work44
towards establishing a public database of clinically useful lines be developed that45

23. 22
contains adequate information to determine the lines’ utility for a particular disease1
therapy.2
3
Some stem cell products entail minimal manipulation and immediate use, whereas other stem4
cell products are intended for future use and thus necessitate storage. Precedents exist for5
two types of stem cell banks: (a) private banks where cells are harvested from an individual6
and stored for future use by that individual or designated family members; and (b) public7
banks that procure, process, store, and deliver cells to matched recipients on a need-based8
priority list, in a model akin to blood banking. The development of banks may be in the9
public interest once stem cell-based treatments are proven effective and become the standard10
of care. The composition of the bank must be constituted with adequate genetic diversity to11
ensure wide access particularly if the government funds such a bank to ensure social justice12
and widespread access.13
14
Careful consideration in the design of the database must be made to promote access to15
appropriate individuals while restricting the release of proprietary information. As it is16
unlikely that any unified repository will be established, it is important to have a global17
nonpartisan authority along the lines of the bone marrow registry or the Blood Bank18
associations to promote harmonization of storage standards and the development of19
consensus SOPs.20
3.2 Preclinical Studies21
22
The purpose of preclinical studies is to (a) provide evidence of product safety and (b)23
establish proof-of-principle for therapeutic effects. International research ethics policies, such24
as the Declaration of Helsinki and the Nuremberg Code, strongly encourage the performance25
of animal studies prior to clinical trials. Before initiating clinical studies with stem cells in26
humans, researchers should have persuasive evidence of clinical promise in appropriate in27
vitro and/or animal models. A fundamental principle here is that preclinical studies must be28
rigorously designed, reported, reviewed independently and subject to regulatory oversight29
and reported, prior to initiation of clinical trials. This helps ensure that trials are scientifically30
and medically warranted.31
32
Cell-based therapy offers unique challenges for preclinical studies. In many cases33
homologous cells in the same species are unavailable. Immune-suppressed animal models,34
while useful, do not permit an understanding of the effect of the immune system on35
transplanted cells. Since transplanted cells can change after transplantation in unpredictable36
ways, extrapolating from an animal model to humans is even more challenging than for small37
molecule products.38
3.2.1 General Considerations39
Animal Welfare40
Recommendation 3.2.1.1: Given that research into stem-cell based therapeutic makes41
heavy use of pre-clinical animal models, researchers should adhere to the principles of42
the three Rs– Reduce numbers, Refine protocols, and Replace animals with in vitro or43
non- animal experimental platforms whenever possible.44
45

24. 23
This requirement is not incompatible with replication experiments or ensuring adequate1
statistical power: indeed, these are key steps for ensuring animal experiments support robust2
conclusions. It should also not be interpreted as suggesting that in vitro or non-animal3
platforms are sufficient for supporting clinical investigations. For responsible animal4
research, investigators planning to conduct animal studies using human stem cells and their5
direct derivatives should refer to applicable ethical considerations described by the ISSCR6
Ethics and Public Policy Committee (Appendix 6) and recommendations 2.1.1, 2.1.3.2, and7
2.1.3.3.8
9
Preclinical Study Objectives10
Recommendation 3.2.1.2: Early phase studies should be preceded by rigorous11
demonstration of safety and efficacy in preclinical studies. The strength of preclinical12
evidence demanded for trial launch should be proportionate with the risks, burdens,13
and ethical sensitivities of an anticipated trial.14
15
Efficacy studies- sometimes also called “proof of principle”- provide the scientific rationale16
for proceeding into human trials. More stringent design and reporting standards should be17
demanded where planned trials involve research subjects with less advanced disease; when18
invasive delivery approaches are anticipated; or where cells present greater risk and19
uncertainty. However, prudent use of scientific resources means that even when research20
subjects have advanced disease or risk is modest, studies should rest on sound scientific21
evidence.22
23
Study Validity24
Recommendation 3.2.1.3: All preclinical studies testing safety and efficacy should be25
designed in way that supports a precise, accurate and unbiased measure of clinical26
promise. In particular, studies designed to inform trial initiation should be internally27
valid; they should be representative of clinical scenarios they are intended to model,28
and they should be replicated.29
30
Like clinical trials, preclinical experiments confront many sources of bias and confounding,31
including selection bias and publication bias. For decades, clinical researchers have sought to32
minimize the effects of bias and confounding by using techniques like randomized allocation,33
blinded outcome assessment, or power calculations. Such rigor should also apply in34
preclinical studies intended to support trials. Numerous groups have articulated guidelines35
for designing preclinical studies aimed at supporting trials.(Fisher et al., 2009; Henderson et36
al., 2013; Landis SC et al., 2012) These guidelines recommend that:37
1- researchers should reduce bias and random variation by ensuring their studies a)38
have adequate statistical power; b) use appropriate controls; c) use randomization;39
d) use blinding; e) establish- where appropriate- a dose-response relationship.40
2- researchers and sponsors should ensure preclinical studies model clinical trial41
settings, researchers should: a) characterize disease phenotype at baseline; b) select42
animal models that best match human disease; c) use outcome measures that best43
match clinical outcomes; and d) demonstrate a mechanism for treatment effect.44
3- researchers and sponsors should ensure effects in animals are robust by replicating45
findings- ideally in an independent laboratory and in a different animal system.46

25. 24
4- researchers and sponsors should pre-specify and report whether a study is1
exploratory (i.e. hypothesis generating or aimed at substantiating basic science2
claims) or confirmatory (i.e. using pre-specified hypotheses and protocols and3
powered to support robust claims). Preclinical researchers should only venture4
claims of clinical utility after confirmatory studies.5
3.2.2 Animal Safety Studies6
Human cells will need to be produced under the conditions discussed in Chapter 4, Cell7
Processing and Manufacture. Special attention should be paid to the characterization of the8
cell population, including possible contamination by irrelevant cell types and when necessary9
to the appropriate safeguards for controlling the unrestricted proliferation and/or aberrant10
differentiation of the cellular product and its progeny. Cells grown in culture, particularly for11
long periods or under stressful conditions, may become aneuploid or have DNA12
rearrangements, deletions, and other genetic or epigenetic abnormalities that could13
predispose them to cause serious pathologies such as tumor formation.14
15
Cell characterization16
Recommendation 3.2.2.1: Cells to be employed in clinical trials must first be rigorously17
characterized to assess potential toxicities through in vitro studies and (where possible18
for the clinical condition and tissue physiology to be examined) in animal studies.19
20
Outside of the hematopoietic and stratified epithelia systems there is little clinical experience21
with the toxicities associated with infusion or transplantation of stem cells or their22
derivatives. In addition to known and anticipated risks (e.g. acute infusional toxicity,23
deleterious immune responses, and tumorigenesis), cell-based interventions present risks that24
can only be discovered with experience. Because animal models may not replicate the full25
range of human toxicities associated with cell-based interventions, particular vigilance must26
be applied in preclinical analysis. This section will define toxicities that are likely to be27
unique to stem cells or their progeny.28
29
Release criteria30
Recommendation 3.2.2.2: Criteria for release of cells for transfer to research subjects in31
trials must be designed to minimize risk from culture-acquired abnormalities. Final32
product as well as in-process testing may be necessary for product release.33
34
Given the nature of pluripotent cells and their innate capacity to form teratomas, there is a35
particular concern for the potential tumorigenicity of hESCs and induced pluripotent stem36
cells or their differentiated derivatives. In in-process testing, it will often be important to37
assess karyotypic instabilities.38
39
Tumorigenicity studies40
Recommendation 3.2.2.3: Risks for tumorigenicity must be rigorously assessed for any41
stem cell-based product, especially when extensively manipulated in culture, when42
genetically modified, or when pluripotent.43
44
The plan for assessing risks of tumorigenicity should be reviewed by an independent body45
prior to initial trials. For pluripotent stem cell-derived products, a plan needs to be in place46

26. 25
to minimize persistence of any remaining undifferentiated cells in the final product and to1
demonstrate that level of purity in final product does not result in tumors in long-term animal2
studies.3
4
Biodistribution studies5
Recommendation 3.2.2.4: For all cell-based products, whether injected locally or6
systemically, researchers should perform detailed and sensitive biodistribution studies7
of cells within the local organ as well as at distant sites.8
9
Because of the potential for cells to persist or expand in the body, systemic delivery of cells10
places extra burdens on investigators to understand the nature and extent by which cells11
distribute throughout the body, lodge in tissues, expand and differentiate. Careful studies of12
biodistribution, assisted by ever more sensitive techniques for imaging and monitoring of13
homing, retention and subsequent migration of transplanted cell populations is imperative for14
interpreting both efficacy and adverse events. While rodents or other small animal models are15
typically a necessary step in the development of stem cell-based therapies, they are likely to16
reveal only major toxic events. The similarity of many crucial physiological functions17
between large mammals and humans may favor testing the biodistribution and toxicity of a18
novel cell therapy in at least one large animal model.19
20
Additional histological analyses or banking of organs for such analysis at late time points is21
recommended. Depending on the laws and regulations of the specific country, biodistribution22
and toxicity studies often need to be performed in a GLP (Good Laboratory Practice)23
certified animal facility.24
25
Route of cell administration, local or systemic, homologous or ectopic, can lead to different26
adverse events, and consequently warrant different degrees of regulatory scrutiny. For27
example, local transplantation into organs like the heart or the brain may lead to life-28
threatening adverse events related to the transplantation itself or to the damage that29
transplanted cells may cause to vital structures. Especially in cases where cell preparations30
are infused at anatomic sites distinct from the tissue of origin (for example, for non-31
homologous use), care must be exercised in assessing the possibility of local, anatomically32
specific and systemic toxicities.33
34
Ancillary Therapeutic Components35
Recommendation 3.2.2.5: Before launching high-risk trials or studies with many36
components, researchers should establish the safety and optimality of other37
intervention components, like co-interventions, devices, or surgeries.38
39
Cell-based interventions may involve other components besides cells, such as biomaterials,40
engineered scaffolds, devices, as well as co-interventions like surgery, tissue procurement41
procedures, and immunosuppression. These add additional layers of risk- and can interact42
with each other. If fully implantable devices are used, separate toxicity studies need to be43
carried out for the device and then separate studies will be warranted for the combo44
cell/device product. Many subjects in cell-based intervention studies may be receiving45
immunosuppressants or drugs for managing their disease. These can interact with cells. In46

27. 26
cases where high standards of safety are demanded (e.g. studies involving high risk),1
researchers should test their interaction.2
3
Long-term safety studies4
Recommendation 3.2.2.6: Preclinical researchers should adopt practices to address5
long-term risks, and to detect new and unforeseen safety issues.6
7
Given the probability for long term persistence of cells and the irreversibility of some cell-8
based interventions, testing of the long-term effect of cell transplants in animals is9
encouraged and there should be stipulations in trials designed for long-term follow-up.10
Length of follow up should vary with survival expectancy for patient populations projected11
for study enrollment.12
13
Potential of Stem Cells for Toxicology14
Recommendation 3.2.2.7: Researchers, regulators, and reviewers should exploit the15
potential for using stem cell science to enhance the predictive value of pre-clinical16
toxicology studies.17
18
Stem cell science holds out the prospect of testing toxicology in cell-based systems or19
artificial organs that more faithfully mimic human physiology. Such approaches, though20
unlikely to ever completely substitute for in vivo testing, hold substantial promise for21
reducing burdens imposed on animals in safety testing and improving the predictive value of22
preclinical safety studies.23
3.2.3 Animal Efficacy Studies24
Given the goals of stem cell-based therapy in tissue repair or disease eradication, preclinical25
studies should ideally demonstrate evidence of a therapeutic effect (or proxy) in a relevant26
animal model for the clinical condition and the tissue physiology to be studied. Mechanistic27
studies utilizing cells isolated and/or cultured from animal models or diseased human tissues28
are critical for defining the underlying biology of the cellular therapy. A complete29
understanding of the biological mechanisms at work after stem cell transplantation in a30
preclinical model is not a prerequisite to initiate human experimentation, especially in the31
case of serious and untreatable diseases for which efficacy and safety have been32
demonstrated in relevant animal models and/or in approved and conclusive human studies33
with the same cell source.34
35
Efficacy Evidence for Initiating Trials36
Recommendation 3.2.3.1: Trials should generally be preceded by compelling preclinical37
evidence of clinical promise in well-designed studies. Animal models suited to the38
clinical condition and the tissue physiology should be used, unless there is conclusive39
evidence of efficacy using similar products against similar human diseases.40
41
Rigorous preclinical testing in animal models is especially important for stem cell-based42
approaches, because cell therapies have distinctive pharmacological characteristics. Before43
clinical testing, preclinical evidence should meet the following four conditions: 1) it should44
establish a mechanism of action, 2) it should establish optimal conditions for applying the45
cell-based intervention (e.g. dose, co-interventions); 3) it should demonstrate ability to46

28. 27
modify disease or injury when applied in suitable animal systems, and 4) such disease1
modification or injury control is of sufficient magnitude and durability to be clinically2
meaningful.3
4
The need for animal models is especially strong in the case of extensive ex vivo manipulation5
of cells and/or when the cells have been derived from pluripotent stem cells. It should be6
acknowledged, however, that preclinical assays including studies in animal models may7
provide limited insight into how transplanted human cells will behave in human recipients8
due to the context- dependent nature of cell behavior and the recipient’s immune response.9
10
Small animal studies11
Recommendation 3.2.3.2: Small animal models should be used to assess the12
morphological and functional recovery caused by cell-based interventions, the13
biological mechanisms of activity, and to optimize implementation of an intervention.14
15
Immune-deficient rodents can be especially useful to assess human cell transplantation16
outcomes, engraftment in vivo, stability of differentiated cells, and cancer risk. Many small17
animal models of disease (for example rodents) can faithfully reproduce aspects of human18
diseases, although there are considerable limitations. Small animal studies should also use19
standard potency assays that quantify cell numbers required for large animal studies and20
subsequent trials.21
22
Large animal studies23
Recommendation 3.2.3.3: Large animal models should be used for stem cell research24
related to diseases that cannot be sufficiently addressed using small animal models25
where anatomical factors are relevant for evaluation, where large animals are believed26
to better emulate human pathology than small animal models, or where risks of27
anticipated human clinical trials are high.28
29
Large animals are often better representations of clinical systems insofar as they are often30
genetically outbred, anatomically more similar, and generally immunocompetent. They31
provide occasions to test co-interventions used in trials (e.g. adjunctive immunosuppressive32
drug therapy) or the compatibility of surgical devices cell products. They also may be33
essential to evaluate issues of scale up, or anatomical factors that are likely to mediate a34
therapeutic effect (e.g. bone in a load-bearing model).35
36
The need for invasive studies in non-human primates should be evaluated on a case-by-case37
basis, and performed only if trials are expected to present high risk, and where nonhuman38
primates are expected to provide information about cell-based interventions not unobtainable39
with other models.40
41
All studies involving the use of non-human primates must be conducted under the close42
supervision of qualified veterinary personnel with expertise in their care and their unique43
environmental needs. Particular care should be taken to minimize suffering and maximize44
the value of studies by using rigorous designs and reporting results in full.45

29. 28
3.2.4 Transparency and Publication1
Recommendation 3.2.4.1: Sponsors, researchers, and clinical investigators should2
publish preclinical studies in full, and in ways that enable an independent observer to3
interpret the strength of the evidence supporting the conclusions.4
5
Publication of preclinical studies serves many ends. It enables peer review of clinical6
research programs, thus enhancing risk/benefit in trials. It redeems the sacrifice of animals7
by disseminating findings from studies. It enables more sophisticated interpretation of8
clinical trial results. It also makes possible the evaluation of preclinical models and assays,9
thus promoting a more effective research enterprise. Many studies show biased patterns of10
preclinical publication. Preclinical studies should be reported in full regardless of whether11
they confirm, disconfirm, or are inconclusive with respect to the hypothesis they are testing.12
The Guidelines recognize that publication may reveal commercially sensitive information13
and therefore allow for a reasonable delay. Nevertheless, preclinical studies supporting a14
trial should be published before the first report of trials. Animal studies should be published15
according to well-recognized standards, such as ARRIVE criteria- (Animal Research:16
Reporting In Vivo Experiments; these reporting guidelines have been endorsed by leading17
biomedical journals).(Kilkenny C et al., 2010)18
3.3 Clinical Research19
20
Clinical research and trials of experimental interventions are an essential step in translating21
cell-based treatments. However, they require participation of human subjects, whose rights22
and welfare must be protected. They also generate information that will be used to guide23
important decisions for patients, clinician scientists and policy makers. The integrity of this24
information must be safeguarded.25
26
Sponsors, investigators, host institutions, and regulators bear responsibility for ensuring the27
ethical conduct of clinical trials. In addition, members of the broader research community28
have responsibility for encouraging ethical research conduct. As with all clinical research,29
clinical trials of stem cell-based interventions must follow internationally accepted principles30
governing the ethical design and conduct of clinical research and the protection of human31
subjects. (Department of Health and Education and Welfare, 1979; European Parliament and32
Council of the European Union, 2001; World Medical Association, 1964) Key requirements33
include adequate preclinical data, oversight, peer review by an expert panel independent of34
the investigators and sponsors, fair subject selection, informed consent, research subject35
monitoring, auditing of study conduct, trial registration and reporting. However, there are a36
number of important stem cell-related issues that merit special attention.37
38
Some interventions, like assisted reproduction technologies, present challenges for standard39
trial designs and may be better evaluated using registries and innovative care pathways.40
Such pathways should nevertheless involve a prespecified protocol, independent review for41
scientific merit and ethics, and a plan for reporting. What follows in this section pertains to42
trials as well as observational studies and innovative care pathways.43

30. 29
3.3.1 Oversight1
The overarching goals of research oversight is to ensure that a clinical trial is likely to be2
safe, protect human subjects, have scientific merit, and that it is designed and carried out in a3
manner that will yield credible data that will enhance scientific and medical understanding.4
5
Prospective Review6
Recommendation 3.3.1.1: All studies involving clinical applications of stem cell based7
interventions must be subject to prospective review, approval, and ongoing monitoring8
by independent human subjects committees.19
10
Independent prospective review is critical for establishing the ethical basis of systematic11
human investigation, regardless of funding source. It minimizes conflicts of interest (both12
financial and non-financial) that can prejudice research design; it maximizes the alignment of13
the goals of the research with the subjects’ rights and welfare; and it promotes valid informed14
consent.15
16
Independent evaluation may also occur through other groups, including granting agencies,17
local peer review, ethics committees, and data and safety monitoring boards. To initiate stem18
cell-based clinical trials, investigators must follow and comply with local and national19
regulatory approval processes.20
21
Expert Review of Trials22
Recommendation 3.3.1.2: The review process for stem cell-based clinical trials should23
ensure that protocols are vetted by independent and disinterested experts who are24
competent to evaluate (a) the in vitro and in vivo preclinical studies that form the basis25
for proceeding to a trial and (b) the design of the trial, including the adequacy of the26
planned end-points of analysis, statistical considerations, and disease-specific issues27
related to human subjects protection.28
29
Peer review should also judge whether the proposed stem cell-based clinical study is likely to30
lead to important new knowledge or an improvement in health. Comparing the relative value31
of a new stem cell intervention to established modes of therapy is integral to the review32
process. Peer-review should be informed where feasible by a systematic review of existing33
literature. If decisions must be made based solely on expert opinion because no relevant34
literature is available, this should be described explicitly in the recommendations regarding a35
particular study.36
3.3.2 Standards for Ethical Conduct37
Systematic Appraisal of Evidence38
Recommendation 3.3.2.1: Launch of trials should be supported by a systematic39
appraisal of evidence supporting the intervention.40
Systematic review ensures that decision-making is supported by a transparent and complete41
synthesis of evidence. It should consist, at a minimum, of a synthesis of unpublished studies42
provided by the investigators, as well as a systematic search and synthesis of published43
1 In some jurisdictions these are known as research ethics committees, institutional
review boards, research ethics boards, and ethics committees.

31. 30
studies testing the intervention in animal systems. For early phase studies, such systematic1
review will mostly involve synthesizing basic and preclinical investigations; for late stage2
studies, systematic review is supplemented by clinical evidence. Systematic review should3
also be informed by accessing and synthesizing findings involving the testing of similar4
intervention strategies. Trial brochures should summarize the information gathered from5
systematic review without any bias.6
7
Risk-Benefit Analysis8
Recommendation 3.3.2.2: Risks should be identified and minimized, unknown risks9
acknowledged, and potential benefits to subjects and society estimated. Studies must10
anticipate a favorable balance of risks and benefits.11
12
Efficient designs that minimize risks and include the smallest number of subjects to properly13
answer the scientific question(s) at hand should be employed. To minimize risks, eligibility14
criteria in prelicensure stages should be designed with consideration of potential co-15
morbidities that may increase risk or modify the risk-benefit ratio. Studies should have16
appropriate correlative studies to ensure that the maximum possible information on the safety17
and activity of the approach being tested is obtained from each research subject.18
19
Research Subjects Lacking Consent Capacity20
Recommendation 3.3.2.3: When testing interventions in populations that lack capacity21
to provide valid informed consent, risks from study procedures should be limited to no22
greater than minor increase over minimal risk unless procedure risks are exceeded by23
the prospect of therapeutic benefit.24
25
Stem cell clinical trials frequently involve populations- like children or persons with26
advanced central nervous system disorders- who lack capacity to provide valid informed27
consent. Because such individuals cannot protect their own interests, they require extra28
protections from research risk. This recommendation pertains to risks that lack a therapeutic29
justification- for example, tissue biopsies to test biodistribution, sham procedures, or30
withdraw of standard treatments to monitor response during unmedicated periods. Such31
procedures should not exceed minor increase over minimal when trial populations lack32
capacity to provide valid informed consent. Because definitions of minimal risk vary by33
jurisdiction, researchers should adhere to policies defined by local institutional review34
committees, or otherwise consider minimal risk as “risk that is no greater than that associated35
with routine medical or psychological examination”.36
37
Objectives of Trials38
Recommendation 3.3.2.4: A stem cell-based intervention must aim at being clinically39
competitive with or superior to existing therapies or occupy a unique therapeutic niche.40
Being clinically competitive necessitates having reasonable evidence that the nature of41
existing treatments pose some type of burden related to it that would likely be overcome42
with the cell-based intervention should it prove to be safe and efficacious.43
44
Genetic and acquired diseases differ widely in their degree of disability, morbidity, and their45
available therapeutic options. These facts have a crucial impact on the decision to proceed to46

32. 31
clinical application with a novel stem cell-based approach, which is itself experimental and1
risky.2
3
Subject Selection.4
Recommendation 3.3.2.5: Individuals who participate in clinical stem cell research5
should be recruited from populations that are in a position to benefit from the results of6
this research. Groups or individuals must not be excluded from the opportunity to7
participate in clinical stem cell research without rational justification.8
9
Well-designed clinical trials and effective stem cell-based therapies should be accessible to10
patients without regard to their financial status, insurance coverage, or ability to pay. In stem11
cell-based clinical trials, the sponsor and principal investigator should make reasonable12
efforts to secure sufficient funding so that no person who meets eligibility criteria is13
prevented from enrollment because of his or her inability to cover the costs of the14
experimental treatment.15
16
Informed Consent.17
Recommendation 3.3.2.6: Informed consent must be obtained from potential subjects or18
their legally authorized representatives. Reconsent of subjects is warranted if19
substantial changes in risks or benefits of a study intervention or alternative treatments20
emerge over the course of investigation.21
22
Culturally sensitive, voluntary informed consent is a necessary component in the ethical23
conduct of clinical research and the protection of human subjects. Subjects should be made24
aware that their participation is voluntary and not necessary for their continued clinical care,25
and that participation or non-participation will not interfere with their ongoing clinical care.26
In addition, consent discussions should emphasize that once the therapy is given it cannot be27
retrieved or removed. Specific consent challenges in early phase trials are discussed below.28
29
Assessment of Capacity30
Recommendation 3.3.2.7: Prior to obtaining consent from potential subjects who have31
diseases or conditions that are known to affect cognition, their capacity to consent32
should be assessed formally.33
34
Subjects and their conditions should not be excluded from biomedical advances involving35
stem cells. At the same time, such subjects should be recognized as especially vulnerable,36
and steps should be taken to involve guardians or surrogates who are qualified and informed37
to make surrogate research judgments and to provide other protections.38
39
Privacy40
Recommendation 3.3.2.8: Research teams should make strong efforts to preserve the41
privacy of study subjects.42
43
Privacy is an important value in many settings. Moreover, there are longstanding professional44
obligations to maintain confidentiality in medical care and research. Given the high profile of45
many stem cell-based intervention trials, it is particularly important for research teams to take46

33. 32
steps to protect the privacy of research subjects. For instance, research data should1
maintained in secure charts or databases with access restricted to study staff and agencies2
who have a regulatory right to review charts.3
4
Patient Funded Trials5
Recommendation 3.3.2.9: Patient sponsorship is an acceptable funding mechanism6
provided studies are independently reviewed for scientific merit, integrity and priority.7
8
Patient-funded trials present opportunities for patients to directly engage in the research9
process and fund work that public and industry sponsors are unwilling to undertake.10
Nevertheless, they present ethical and policy challenges. Patient funders may press for study11
designs that eliminate design elements, like randomization to a comparator arm, eligibility or12
exclusion criteria that are critical for promoting scientific validity and patient welfare.13
Patient funders might also lack the skill to distinguish meritorious protocols from those that14
are scientifically dubious. Finally, patient-funded trials may divert resources- such as study15
personnel- from research activities that advance more promising research avenues, or that16
serve less privileged populations. The above liabilities should be managed by requiring that17
patient-funded trial protocols undergo independent review for scientific rationale, priority18
and design. While input from patient communities can greatly enhance the research process,19
decisions concerning the launch, design, conduct, analysis and reporting of studies should be20
insulated from the influence of patient funders.21
3.3.3 Issues Particular to Early Phase Trials22
Initiation of clinical development is a pivotal step in translation. It provides the first23
opportunity to evaluate methods and effects in human beings. It also represents the first24
occasion where human beings are exposed to an unproven intervention. Because early phase25
studies of cell-based interventions involve high levels of uncertainty, investigators, sponsors,26
and reviewers may have very different views about the adequacy of preclinical support for27
trial initiation.28
29
Consent in Early Phase Trials30
Recommendation 3.3.3.1: Consent procedures in any prelicensure phase- but especially31
early phase trials of cell-based therapies should work to dispel research subject32
overestimation of benefit and therapeutic misconception.33
34
Early phase trials involving cell-based interventions generally enroll research subjects who35
have exhausted standard treatment options. In many cases, as in the case of cardiac studies,36
trials enroll individuals who have just experienced a life-altering medical event. Such37
individuals may be prone to overestimating the therapeutic value of study participation,38
overlooking the implications of study participation, or mistaking demarcated research39
procedures for therapeutic ones (“therapeutic misconception”). Investigators should make40
particular efforts to ensure that informed consent is valid. Among approaches that might be41
considered are: conducting informed consent discussions that include an individual who is42
independent of the research team; explaining to prospective subjects that major therapeutic43
benefits in early phase studies are exceedingly rare; testing prospective subjects on44
comprehension before accepting their consent; requiring a “cooling off” period between45
provision of consent discussions and acceptance of consent; avoiding language that has46